Project Summary Alzheimer?s disease (AD) is the 6th leading cause of death in the United States but there is no disease-modifying therapy. Mutations in the Presenilin (PSEN) genes account for ~90% of all causative mutations in familial AD (FAD), highlighting its importance in AD pathogenesis. Findings from our lab and other groups over the last two decades have demonstrated that Presenilin (PS) is essential for learning and memory, synaptic function and neuronal survival, and that PSEN1 mutations cause loss of its essential function and reduction of g-secretase activity. For example, the PSEN1 L435F mutation results in undetectable g-secretase activity in homozygous knock-in mouse brains, genocopies the PS1-null mutation, and causes memory and synaptic impairment as well as age-dependent neurodegeneration. Subsequent structural analysis placed the L435 residue nearest to D257 and D385, the aspartate residues serving as the catalytic core of g-secretase, providing a structural basis for L435F?s severe loss of function phenotypes. Moreover, biochemical studies of 138 PSEN1 mutations from another group showed that ~90% mutations cause loss of g-secretase activity and 30% mutations abolish its activity. In this application, we propose to take the first step in a translational program to develop novel therapies for FAD. Specifically, we propose to test whether introduction of wild-type human PS1 can prevent or ameliorate functional impairments and neurodegeneration caused by PSEN1 mutations using constitutive and inducible transgenes (Aim 1). Among FAD mutations, the PSEN1 E280A mutation is most common and affects ~5000 individuals in an extended Columbian kindred. While the large Columbian kindred provides a unique opportunity to test novel therapies, there is no relevant animal model for preclinical studies. We therefore propose to generate E280A knock-in mice, which recapitulate the human mutation faithfully, and determine the effects of the E280A mutation on PS1 function and g-secretase activity and further test whether introduction of wild-type human PS1 can prevent and ameliorate the phenotypes associated with the E280A mutation (Aim 2). The completion of the proposed study will determine whether introduction of wild-type hPS1 is effective in preventing or ameliorating functional impairments and neurodegeneration caused by PSEN1 mutations.